Synthesis, crystal structure and Hirshfeld surface of ethyl 2-[2-(methylsulfanyl)-5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazol-1-yl]acetate (thiophenytoin derivative)

The dihydroimidazole ring in the title molecule is slightly distorted and the lone pair on the tri-coordinate nitrogen atom is involved in intra-ring π bonding. In the crystal, C—H⋯O hydrogen bonds form inversion dimers, which are connected along the a- and c-axis directions by additional C—H⋯O hydrogen bonds, forming layers parallel to the ac plane.


Chemical context
The family of hydantoin drugs is important in medicinal chemistry because of the wide range of pharmacological activities exhibited, including antibacterial, antidiabetic, antiinflammatory, anticonvulsant, anti-HIV and anticancer properties.Thiohydantoins, sulfur analogues of hydantoins, undergo replacement of one or both carbonyl groups with thiocarbonyl groups.This substitution enables versatile structural modifications, facilitating the customization of thiohydantoins to preferentially adopt specific structural types.Such modifications, achieved by introducing steric bulk, altering hydrophilic or hydrophobic interactions, or promoting stacking, afford control over the molecule's ability to form hydrogen-bonded arrays in the solid state.In particular, phenytoin and thiophenytoin derivatives and diphenylsubstituted hydantoin exhibit significant activity against tonicclonic (grand mal) seizures (Camerman & Camerman, 1971).These chemicals are recognized for their anticonvulsant properties and have diverse pharmacological applications, including antifungal, herbicidal, anti-inflammatory, anti-HIV, antimicrobial, anticancer, and antibacterial activities, which vary based on the specific substitutions on the hydantoin ring (Cho et al., 2019;Allah et al., 2024;El Moutaouakil Ala Allah et al., 2024a).The significance of this scaffold in drug discovery is underscored by several clinically used medications, including phenytoin, nitrofurantoin, and enzalutamide (Patocka et al., 2020).Given the wide range of therapeutic applications for such compounds, we have previously reported a route for the preparation of thiophenytoine derivatives using N-alkylation reactions carried out with ethyl bromoacetate (Guerrab et al., 2020(Guerrab et al., , 2022;;Missioui et al. 2022).A similar approach yielded the title compound, C 20 H 20 N 2 O 3 S (Fig. 1).In addition to the synthesis, we also report the molecular and crystal structure along with a Hirshfeld surface analysis.

Structural commentary
The dihydroimidazole ring is slightly distorted with C1 located 0.0166 (10) A ˚to one side of the mean plane and C14 positioned 0.0199 (10) A ˚on the other side (r.m.s.deviation of the fitted atoms = 0.0143 A ˚).The ethoxy group is disordered over two resolved sites in a 0.741 (7)/0.259(6) ratio.The sum of the angles about N2 is 359.89 (15) � , indicating participation of its lone pair in N!C � bonding.This occurs to a slightly greater extent with C14 as the N2-C14 bond length is 1.371 (2) A ẘhile the N2-C15 bond length is 1.406 (2) A ˚.By contrast, the N2-C17 bond length is 1.445 (2) A ˚.The C16 methyl group lies nearly in the plane of the dihydroimidazole ring as the C16-S1-C15-N2 torsion angle is À 176.94 (14) � but the ester substituent is directed well out of this plane since the C15-N2-C17-C18 torsion angle is À 76.6 (2) � (Fig. 2).The rotational orientation of the C8� � �C13 phenyl ring is partially determined by the intramolecular C9-H9� � �O1 hydrogen bond (Fig. 2).

Supramolecular features
In the crystal, inversion dimers are formed by paired C17-H17A� � �O1 hydrogen bonds.The dimers are formed into chains extending along the c-axis direction by weak C5-H5� � �O2 hydrogen bonds and the chains are linked by weak C11-H11� � �O1 hydrogen bonds (Table 1) along the aaxis direction into layers parallel to the the ac plane.The layers pack with normal van der Waals contacts (Fig. 2).

Database survey
A search of the Cambridge Structural Database (CSD; updated to May 31, 2024; Groom et al., 2016) with the fragment shown in Fig. 3 yielded ten hits including those with methyl (YEYYA; El Moutaouakil Ala Allah et al., 2023), ethyl (HOPQAI;Allah et al., 2024a), n-propyl (RIJZIW: Akrad et    Guerrab et al., 2023).In all cases, the dihydroimidazole ring is planar with the maximum deviation of a fitted atom from the mean plane ranging from 0.006 (1) A ˚(HOPQAI, r.m.s.deviation of the fitted atoms = 0.001 A ˚) to 0.023 (2) A (RAHGUF, r.m.s.deviation of the fitted atoms = 0.002 A ˚) for those not have a ring fused to it and up to 0.029 (2) A (IMTHZN01, r.m.s.deviation of the fitted atoms = 0.002 A ˚) where a fused ring is present.Particularly where the second ring size is relatively small (DIYRAE, FURFED, IMTHZN and IMTHZN01), it is likely that strain from the ring fusion contributes to the greater deviation from planarity.With the exception of the four just mentioned where geometrical constraints require it, all structures have the carbon attached to sulfur in the side chain very close to the mean plane of the dihydroimidazole ring as in the title molecule.The same group of structures has the �-carbon of the substituent on nitrogen oriented well out of that plane.

Hirshfeld surface analysis
A Hirshfeld surface analysis of the intermolecular interactions of the title molecule was carried out with Crystal Explorer 21.5    (Spackman et al., 2021) and descriptions of the graphical output and its interpretation have been published (Tan et al., 2019).The d norm surface calculated over the range À 0.2373 to 1.3807 in arbitrary units is shown in Fig. 4a together with four neighboring molecules illustrating the weak C5-H5� � �O2 and C11-H11� � �O1 hydrogen bonds while Fig. 4b shows the surface calculated over the curvature function.The latter shows that there are no extensive flat regions about the molecule, consistent with the absence of �-stacking interactions.Fig. 5 shows the 2-D fingerprint plot of all intermolecular interactions and those delineated into contributions from H� � �H, C� � �H/H� � �C, O� � �H/H� � �O and S� � �H/H� � �S interactions.Here, the H� � �H interactions comprise 56.4% of the total, consistent with the high hydrogen content of the molecule and the shape, which has many of the hydrogen atoms pointing outwards from the center of gravity.The other significant contributions are from C� � �H/H� � �C, O� � �H/H� � �O and S� � �H/H� � �S contacts at 20.5%, 14.7% and 4.9%, respectively.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms were included as riding contributions in idealized positions with isotropic displacement parameters tied to those of the attached atoms.
The ethoxy group is disordered over two sites in a 0.741 (7)/ 0.259 (6) ratio.The two components were refined with restraints to make their geometries be comparable.

Special details
Geometry.All esds (except the esd in the dihedral angle between two l.s.planes) are estimated using the full covariance matrix.The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry.An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s.planes.

Figure 1
Figure 1The title molecule with the labeling scheme and 30% probability ellipsoids.The intramolecular C-H� � �O hydrogen bond is depicted by a dashed line and only the major component of the disorder is shown.

Figure 2
Figure 2Packing viewed along the c-axis direction giving end views of two adjacent layers.The C-H� � �O hydrogen bonds are depicted by dashed lines and non-interacting hydrogen atoms are omitted for clarity.

Figure 3
Figure 3The search fragment used for the database survey.

Figure 4 The
Figure 4The Hirshfeld surface plotted over (a) d norm and (b) curvature with four neighboring molecules.C-H� � �O hydrogen bonds are depicted by green dashed lines.
Figure 6Synthesis of the title compound.

Table 2
Experimental details.